Effect of celastrol on the progression of polycystic kidney disease in a Pkd1-deficient mouse model
Introduction
Autosomal dominant polycystic kidney disease (ADPKD) is a common disease, caused by mutations in PKD1, PKD2, and other genes, such as GANAB [32]. Renal function in patients with ADPKD may decline progressively because of the destruction of normal kidney structures caused by the growth of renal cysts [2]. ADPKD pathogenesis involves abnormal cell proliferation, fluid secretion, ciliary signaling, and extracellular matrix defects [31]. Other cellular abnormalities, such as inflammation and metabolic reprogramming, may contribute to cyst expansion and disease progression in ADPKD [15,45]. Inhibition of the cyclic adenosine monophosphate (AMP) pathway by using tolvaptan, a vasopressin V2 receptor antagonist, in patients with ADPKD reduced cyst growth and improved renal function [42]. However, whether a combination of treatments targeting metabolic reprograming, inflammation, and fibrosis are also beneficial in alleviating ADPKD remains unknown thus far [5].
Celastrol and triptolide represent two different classes of compounds that are isolated from roots of the Chinese herb thunder god vine [26,35]. Triptolide inhibits the early phase (up to postnatal day 8) of cyst growth through the suppression of cell proliferation and restoration of cytosolic Ca2+ release in Pkd1 knockout mice [[21], [22], [23]]. In an observational cohort of patients with proteinuric ADPKD, treatment with triptolide was associated with a reduction in proteinuria and improvement in total kidney volume [7]. Contrary to those of triptolide, the effects of celastrol on the progression of ADPKD have not been reported.
Celastrol, a naturally occurring pentacyclic triterpene, has attracted considerable interest because it can be used for treating inflammation, cancers, obesity, and autoimmune diseases [3,12,17,20,36]. Small quantities of celastrol are extracted from Tripterygium wilfordii or other members of the Celastraceae (bittersweet) family [10]. Celastrol modulates proteasome activity [48], heat shock responses [38,50], and the nuclear factor kappa B (NF-κB) signaling pathway [18]. Furthermore, celastrol could reduce obesity by sensitizing leptin receptors in hyperleptinemic diet-induced obese mice [25], suggesting that celastrol plays a role in modulating metabolic processes. Therefore, we hypothesize that celastrol is a potential therapeutic agent for ADPKD.
In this study, we investigated the effects of celastrol treatment on renal cyst formation and disease progression in a Pkd1-deficient mouse model of ADPKD. We also determined the effects of celastrol on renal inflammation and fibrosis in the cystic kidneys of the Pkd1 miR mice.
Section snippets
Pkd1 miRNA mouse line
Pkd1 miRNA transgenic (Pkd1 miR TG) mice with a C57BL/6 background were provided by Prof Si-Tse Jiang (National Rodent Model Resource Center, Taiwan) [43], and the wild-type littermates were used in the comparison study. All the mice were housed in the Chang Gung Memorial Hospital Animal Center (Taoyuan, Taiwan) under climate-controlled conditions with a 12-h light-dark cycle. They had free access to standard laboratory food and drinking water. The animal experiment protocols were approved by
Effects of celastrol on cyst formation in the Pkd1 miR TG mice
We used a Pkd1 miR TG mouse model to determine the effects of celastrol on renal cyst formation. The Pkd1 miR TG mice progressively developed cyst in both kidneys, interstitial fibrosis, inflammation, and elevated BUN levels in the first 3 months and exhibited longer survival durations than did the previous models [13,43]. The slow development of renal cysts in this model provided an opportunity to examine the natural progression of ADPKD, which is similar to that of a chronic kidney disease.
Discussion
Traditional medicines are increasingly being used as valuable sources for developing new therapeutic agents [10]. In this study, we demonstrated that celastrol, a natural anti-inflammatory compound, partially ameliorates the progression of renal cysts in a mouse model of ADPKD. Furthermore, the beneficial effects were associated with AMPK pathway activation. To our knowledge, this is the first report to focus on the effects of celastrol on the progression of ADPKD.
In this study, rather than an
Conclusions
Low doses of celastrol ameliorate renal inflammation and the cyst burden in the Pkd1-deficient mice. These results indicate that celastrol is a potent anti-inflammatory agent and could be a natural AMPK enhancer. However, celastrol has only modest effects on the progression of PKD and has a narrow therapeutic window. Further studies are still needed to clarify whether celastrol has therapeutic potential for ADPKD.
The following is the supplementary data related to this article.
Acknowledgments
We thank Dr. Hui-Ping Chien, Hui-Wen Chiang, Yi-Ching Ko, Chiung-Tzeng Huang, Jing-Shiuan Liu, and Tsu-Lin Ma for their excellent technical assistance. We also thank Prof Si-Tse Jiang for providing the Pkd1 miR TG mice and Taiwan National Laboratory Animal Center for their technical support in breeding and testing services. This work was supported by grants from Chang Gung Memorial Hospital (CMRPG3E2002, CMRPG3H0071) and the Ministry of Science and Technology of Taiwan (102-2314-B-182-045,
Contributions
M.-Y.C., Y.-C.T., C.-C.H., and C.-W.Y. conceived and designed the experiments. M.-Y.C., T.-D.C., H.-H.H., and K.-H. C. performed the experiments.
C.-Y. H., C.-Y.L., H.-Y.Y., and Y.-C.C. analyzed the data.
M.-Y.C. drafted the manuscript.
Conflict of interest statement
The author(s) declare no competing financial interests.
References (52)
- et al.
Patterns of kidney function decline in autosomal dominant polycystic kidney disease: a post hoc analysis from the HALT-PKD trials
Am. J. Kidney Dis.
(2018) - et al.
Triptolide-containing formulation in patients with autosomal dominant polycystic kidney disease and proteinuria: an uncontrolled trial
Am. J. Kidney Dis.
(2014) - et al.
A mechanistic overview of triptolide and celastrol, Natural Products from Tripterygium wilfordii Hook F. Frontiers in pharmacology
Front. Pharmacol.
(2018) - et al.
Molecular understanding and modern application of traditional medicines: triumphs and trials
Cell
(2007) - et al.
Inhibition of inflammation with celastrol fails to improve muscle function in dysferlin-deficient A/J mice
J. Neurol. Sci.
(2015) - et al.
Celastrol suppresses breast cancer MCF-7 cell viability via the AMP-activated protein kinase (AMPK)-induced p53-polo like kinase 2 (PLK-2) pathway
Cell. Signal.
(2013) - et al.
Treatment of obesity with celastrol
Cell
(2015) - et al.
Sex differences in subacute toxicity and hepatic microsomal metabolism of triptolide in rats
Toxicology
(2010) - et al.
Association of urinary biomarkers with disease severity in patients with autosomal dominant polycystic kidney disease: a cross-sectional analysis
Am. J. Kidney Dis.
(2010) Making sense of polycystic kidney disease
Lancet
(2017)
Mutations in GANAB, encoding the glucosidase IIalpha subunit, cause autosomal-dominant polycystic kidney and liver disease
Am. J. Hum. Genet.
Celastrol: molecular targets of Thunder God Vine
Biochem. Biophys. Res. Commun.
Celastrol ameliorates murine colitis via modulating oxidative stress, inflammatory cytokines and intestinal homeostasis
Chem. Biol. Interact.
Celastrol, an oral heat shock activator, ameliorates multiple animal disease models of cell death
Cell Stress Chaperones
A new mechanism of inhibition of IL-1beta secretion by celastrol through the NLRP3 inflammasome pathway
Eur. J. Pharmacol.
Characterization of celastrol to inhibit hsp90 and cdc37 interaction
J. Biol. Chem.
Celastrol ameliorates liver metabolic damage caused by a high-fat diet through Sirt1
Mol. metab.
Renal CD14 expression correlates with the progression of cystic kidney disease
Kidney Int.
Celastrol protects against Antimycin A-induced insulin resistance in human skeletal muscle cells
Molecules
Decrease of CD68 synovial macrophages in celastrol treated arthritic rats
PLoS One
Metformin inhibits cyst formation in a zebrafish model of Polycystin-2 deficiency
Sci. Rep.
Targeting new cellular disease pathways in autosomal dominant polycystic kidney disease
Nephrol. Dial. Transplant.
Endothelin B receptor blockade accelerates disease progression in a murine model of autosomal dominant polycystic kidney disease
J. Am. Soc. Nephrol.
2-Deoxy-d-glucose ameliorates PKD progression
J. Am. Soc. Nephrol.
Targeted delivery of celastrol to mesangial cells is effective against mesangioproliferative glomerulonephritis
Nat. Commun.
Translational research in ADPKD: lessons from animal models
Nat. Rev. Nephrol.
Cited by (9)
A scalable organoid model of human autosomal dominant polycystic kidney disease for disease mechanism and drug discovery
2022, Cell Stem CellCitation Excerpt :Therefore, rapamycin was added as a potential inhibitor of cyst formation. Two compounds shown to inhibit cyst formation in ADPKD mouse models: carfilzomib, a proteasome inhibitor, and celastrol, a pentacyclic triterpene (Booij et al., 2020; Chang et al., 2018; Fedeles et al., 2011), were added as further potential inhibitory controls. Additionally, we also examined the effects of forskolin and blebbistatin, compounds previously identified to enhance cystogenesis (Czerniecki et al., 2018; Low et al., 2019).
Transgenic animals in research and industry
2020, Animal Biotechnology: Models in Discovery and TranslationInsights Into the Molecular Mechanisms of Polycystic Kidney Diseases
2021, Frontiers in PhysiologyNanotechnology-Based Celastrol Formulations and Their Therapeutic Applications
2021, Frontiers in PharmacologyApplications of Herbal Medicine to Treat Autosomal Dominant Polycystic Kidney Disease
2021, Frontiers in Pharmacology